Immediate release tablet cores of insoluble drugs having sustained-release coating

ABSTRACT

A controlled release tablet for oral administration is disclosed which has a tablet core including an insoluble therapeutically active agent having an aqueous solubility of less than or equal to about 5 mg/ml in a sufficient amount to render a therapeutic effect. The core provides rapid release of said therapeutically active agent upon exposure to aqueous solutions. The tablet core is coated with a controlled release coating permitting sustained release of said therapeutically active agent when said coated tablet is exposed to aqueous solutions.

This is a divisional of application Ser. No. 08/156,460 filed Nov. 23,1993 U.S. Pat. No. 5,500,227.

BACKGROUND OF THE INVENTION

The maximum time of effectiveness of many oral dosage forms is only afew hours. In order to maximize patient compliance, it is consideredvery desirable to reduce the frequency of dosing, thereby reducing thenumber dosage forms (e.g., tablets, etc.) a patient must take in orderto attain effective therapy.

Sustained release formulations for drugs have become increasinglyavailable. This is true especially when the particular drug isrelatively soluble. Various formulation techniques have been used forproviding a sustained release formulation of soluble drugs. In many suchformulations, a drug-containing particle is coated with a coating layeror is dispersed within a continuous matrix such as a polymeric matrix.The coating layer or the matrix comprises a relatively insolublematerial or materials, and the release of the drug is controlled bymeans of the resistance of the coating layer or matrix against thediffusion of the drug therethrough. The release of the drug from suchformulations is driven, e.g., by the gradient of the drug concentrationresulting from penetration of, e.g., gastric fluid, by diffusion intothe formulation.

The task of preparing controlled release formulations of relativelyinsoluble drugs has proven to be more difficult, however. Examples ofsuch relatively insoluble drugs include acetaminophen, naproxen andindomethacin.

In part because the bioavailability of relatively insoluble drugs ishighly dependent on the particle size of the drug or its specificsurface area, much of the prior art directed to the provision ofcontrolled release dosage forms for relatively insoluble drugs involvesthe use of pellets, beads or spheres having a relatively small particlesize.

For example, U.S. Pat. No. 4,840,799 (Appelgren, et al.) is related tothe preparation of rapidly disintegrating core granulates of slightlysoluble drugs (solubility of <1000 mg/l) wherein the drug in particulateform is coated with a layer of an emulsifier/tensile having the sameHLB-value as the solubility of the drug. The product is said to providehigh bioavailability via the rapid disintegration and release of thedrug at a suitable location along the gastrointestinal tract.

With regard to controlled (slow) release formulations, in U.S. Pat. No.4,752,470 (Mehta), a controlled release indomethacin formulation isdescribed wherein coated pellets of indomethacin of only one type aredescribed. The pellet is said to release indomethacin in both immediateand sustained release form. The pellet consists of a non-pareil beadwhich supports indomethacin and a binder agent, which is then coatedwith a mixture of hydroxypropyl cellulose, ethyl cellulose and aplasticizer. The loaded pellets are preferably composed of 2-10% byweight binder, and about 5-30% by weight indomethacin. The pellets arethen coated with 0.5-10% by weight of the mixture of hydroxypropylcellulose and ethyl cellulose. The ratio of ethyl cellulose tohydroxypropyl cellulose depends upon the desired controlled releasecharacteristics.

U.S. Pat. No. 5,133,974 (Paradissis, et al.) describes an extendedrelease formulation which consists of a mixture of 0-50% immediaterelease particles containing a drug, an inert substrate and bindercoated with talc, and up to 100% of an extended release particlecomprising the immediate release particle coated with a dissolutionmodifying system containing plasticizers and a film forming agent.Optionally, additionally a drug is included in the coating.

On the other hand, U.S. Pat. No. 4,892,741 (Ohm, et al.) describes acoated tablet consisting of a core which contains a dihydropyridinehaving a low aqueous solubility (e.g., nifedipine, nitrendipine,nimodipine and nisoldipine) in rapid-release form and a coating aroundthe core containing a dihydropyridine in slow-release form. Therapid-release core preferably contains the active compound in amorphousform or in a finely grounded or micronized crystalline form. Thegranules for the coating of the tablet contain 10-99% of hydrophilicgel-forming polymers together with the drug. The coating is carried outon a press coater.

U.S. Pat. No. 3,184,386 describes tablets having a rapid-releasepreparation in the outer coating. The core primarily has a function ofnot allowing the surface of the outer coating containing the drug tobecome too small for release purposes. However, the core does notcontain drug in rapid-release form. Both the central coat and the coreare also described in the examples as slow-release forms of highlysoluble active compounds. U.S. Pat. No. 3,558,768 also describes coatedtablets which contain drug in the slow-release form both in the core andin the coating.

It has been found that, when attempting to prepare controlled-releasetablets of an insoluble drug contained within a controlled releasematrix, such formulations suffer from unacceptable batch to batch anddosage unit to dosage unit dissolution variability which would in turnresult in such products not being commercially viable.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a controlled releaseformulation of a relatively insoluble drug which displays acceptablebatch-to-batch and dosage unit to dosage unit dissolutionreproducibility.

It is another object of the present invention to provide a controlledrelease tablet of a relatively insoluble drug which provides areproducible in-vitro dissolution profile on a batch-to-batch basis.

It is another object of the present invention to provide a method ofpreparing a controlled release tablet of a relatively insoluble drugwhich can be manufactured with relative ease.

The above objects and others are achieved by virtue of the presentinvention, which relates to a controlled release tablet for oraladministration, comprising a core including a therapeutically activeagent (drug) having a solubility of less than or equal to about 5 mg/mlin an amount sufficient to render a therapeutic effect, the coreproviding immediate release of said therapeutically active agent uponexposure to aqueous solution, the immediate release core being coatedwith a sustained release coating.

The present invention further relates to a method for preparing a oralcontrolled release formulation of an insoluble drug, comprising coatingan immediate release tablet core including a therapeutically activeagent in an amount sufficient to render a therapeutic effect, thetherapeutically active agent having a solubility of less than or equalto about 5 mg/ml in an amount sufficient to render a therapeutic effect,with a sustained release coating having a sufficient thickness to causethe therapeutically active agent to be release slowly when exposed to anaqueous solution.

In certain preferred embodiments, the sustained release coatingcomprises an aqueous dispersion of a plasticized hydrophobic polymerselected from the group consisting of ethylcellulose, a polymer orcopolymer of acrylates or methacrylates, and a mixture thereof to aweight gain from about 3 to about 20 percent. Preferably, the coatingtablet cores of the embodiments are cured at a temperature above theglass transition temperature of the plasticized coating and at arequisite relative humidity until an end-point is reached at which thecured coated tablet provides a stable dissolution profile. The endpointis determined by comparing the dissolution profile of the coated tabletimmediately after curing to the dissolution profile of the coated tabletafter exposure to accelerated storage conditions of three months at atemperature from about 37° C. to about 40° C. and a relative humidityfrom about 75% to about 80%.

The present invention also relates to a sustained release tablet fororal administration, comprising an immediate release tablet coreincluding from about 300 mg to about 500 mg acetaminophen, and atherapeutically effective amount of an analgesic agent selected fromhydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine,morphine, buprenorphine, other opioids, salts of any of the foregoing,and mixtures of any of the foregoing, the tablet core being coated witha sufficient amount of a hydrophobic polymer such that the acetaminophenand the analgesic agent are released from the coated tablet over anextended period of time. The immediate release tablet core providing thedissolution of not less than 75% of the acetaminophen in 45 minutes whensaid tablet core is placed in 900 ml 0.1 N hydrochloric acid. Thepresent invention is further related to a sustained release oral soliddosage form comprising an immediate release tablet core comprising aninsoluble therapeutically active agent having a solubility of less thanor equal to about 5 mg/ml and a soluble therapeutically active agentwhich is highly soluble in water relative to said insolubletherapeutically active agent, the immediate release tablet core beingcapable of releasing not less than 75% of said insoluble and saidsoluble therapeutically active agents in 45 minutes when placed in 900ml 0.1 N hydrochloric acid, and an effective amount of a sustainedrelease coating formed over said tablet core. The coating, in certainpreferred embodiments, comprises an aqueous dispersion of a plasticizedhydrophobic polymer selected from the group consisting ofethylcellulose, a polymer or copolymer of acrylates or methacrylates,and a mixture thereof to a weight gain from about 3 to about 20 percent.In certain preferred embodiments, the insoluble therapeutically activeagent is acetaminophen and said soluble therapeutically active agent isselected from the group consisting of hydromorphone, oxycodone,dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, saltsof any of the foregoing, and mixtures of any of the foregoing.

By "immediate release core", it is meant for purposes of the presentinvention that the tablet core containing the therapeutically activeagent(s) meets the disintegration and/or dissolution requirements forimmediate release tablets of the particular therapeutically activeagent(s) included in the tablet core, as set forth in the USP XXII, 1990(The United States Pharmacopeia).

By "sustained release", it is meant for purposes of the presentinvention that the release of the therapeutically active agent occurssuch that blood levels are maintained within a desired therapeutic rangeover an extended period of time, e.g., at least about 8 and preferablyfrom about 12 to about 24 hours. The "dissolution requirements" and"disintegration requirements" referred to above are conducted using theequipment and tests specified in the USP XXII and conducted pursuant tothe individual Official Monographs of USP XXII for the particulartherapeutically active agent(s) included in the tablet core.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the dissolution obtained forExamples 1, 3, 5 and 7;

FIG. 2 is a graphical representation of the dissolution obtained forExamples 2, 4, 6 and 8;

FIG. 3 is a graphical representation comparing the dissolution ofExample 9 to the dissolution obtained for Examples 1, 3, 5 and 7;

FIG. 4 is a graphical representation comparing the dissolution ofExample 10 to the dissolution obtained for Examples 2, 4, 6 and 8;

FIG. 5 is a graphical representation of the dissolution obtained forComparative Example 11; and

FIG. 6 is a graphical representation of the dissolution obtained forComparative Example 12.

DETAILED DESCRIPTION

Once orally administered, solid dosage forms containing one or moredrugs must allow the drug(s) to dissolve in the gastrointestinal tractin order for the drug to be absorbed. The rate and extent of thedissolution of a drug in the gastrointestinal tract can greatlyinfluence the rate and extent of absorption of the drug. It isespecially important that the dosage form have a high bioavailability ofthe drug in order to (1) reduce the total amount of drug which must beadministered to obtain a therapeutic effect, and (2) decrease thebiological variability in the drug levels in the circulation.

The solubility of the solid drug itself can also greatly influence itsabsorption in the gastrointestinal tract and its bioavailability.Compounds with an aqueous solubility of greater than 1% w/v are notexpected to present dissolution-related absorption problems. See, e.g.,Pharmaceutical Dosage Forms--Tablets, Vol. 1, page 13, Edited by H.Lieberman, Marcel Dekker, Inc. ©1980.

While certain highly insoluble drugs may dissolve rapidly in thegastrointestinal tract if provided, e.g., in very fine particulate formand in small doses, it is often the case that such tactics are notpossible. This may be due, for example, to the necessary dosage of thedrug required to obtain a desired therapeutic effect. In such caseswhere the particle size or dosage does not in and of itself provide thenecessary rate and extent of dissolution, efforts must be made throughpharmaceutical formulation considerations to alter the "normal"dissolution of the drug in order to provide an acceptable rate andextent of dissolution in the gastrointestinal tract.

The problems associated with developing a reproducible dissolutionprofile for insoluble drugs has been recognized, e.g., by the UnitedStates Food and Drug Administration (FDA). For example, this Agency hasfor years recognized the difficulty in developing a regulatory policy,based on solid pharmaceutic principles, for scaling-up solid oral dosageform batch sizes. While FDA generally allows firms to employ a minimumbatch size of 100,000 units with the provision for up-scaling by 10 foldon the basis of similar dissolution profiles, and the routine use of abatch size of 10% of the proposed production batch, or 100,000 units,whichever is greater, separate procedures have been proposed forregulating scale-up of dosage forms for very soluble drugs, drugs havinga narrow therapeutic index, and cases where different equipment designsand operating principles are to be employed in the production batchsize. For very soluble drugs, a dissolution profile is all that would berequired. Where equipment of different design or operating principle isemployed, an in-vivo bioavailability study might be required.Quantitative adjustment of a particular dosage form within the aboveranges is considered by FDA to be a relatively minor change.

However, FDA has recognized that changes in particle size, surface areaand/or intrinsic dissolution can have significant effects in thespecifications of the final product, and that end process testingrequirements need to be determined on the basis of the bioavailabilityproblem potential of the drug. See, e.g., FDA/AAPS Workshop Report,"Scale-up Of Immediate Release Oral Solid Dosage Forms", December 1991by Skelly, et al. Thus, for drug substances with an aqueous solubilityof ≦5 mg/ml, a change greater than 10% in mean particle size(distribution remaining approximately the same), surface area, orintrinsic dissolution rate, may be considered to represent a majorchange which might require in vivo bioavailability study. Furthermore,it is recognized that for very slightly soluble drugs with highpermeability (e.g., an extent of absorption into the intestinal tractgreater than 90% in the absence of luminal instability), dissolution islikely the critical variable controlling drug absorption.

Drugs with a dose/solubility volume of greater than or equal to 5 mg/mlare defined as high solubility drugs. For such drugs, dissolution of 85%in 30 minutes, in 900 ml of 0.1 N HCl may be all that is required.

For high permeability-low solubility or high solubility-low permeabilitydrugs, a dissolution profile (15, 30, 45, 60, 120, 180 minutes (or untileither 90% is dissolved, or an asymptote is reached)) in media ofdiffering pH, with a 95% confidence interval encompassing the "referencebatch" (previous market formulation batch having known bioavailabilityor defined clinical efficacy), is required. Profiles should be obtainedin water, 0.1 N HCl, and USP buffer media at pH 4-8, e.g., pH 4.5, 6.5and 7.5. A surfactant may be used if it was in the original application,or can be otherwise justified.

Because of the expected sensitivity of absorption to in vivodissolution, in vivo data are required for low permeability, lowsolubility drugs.

Pursuant to the present invention, it has been surprisingly discoveredthat controlled release formulations of insoluble drugs can be prepared,which formulations provide the requisite batch-to-batch reproducibilityand scale-up reproducibility with regard to in-vitro dissolution, viaovercoating immediate release tablet cores containing the insoluble drugwith a controlled release film coating. This procedure provides relativeease with regard to process steps and formulation requirements and costscompared to other attempts at providing controlled release dosage formsof such drugs.

Insoluble drugs which may be used in conjunction with the presentinvention include, therefore, those drugs which have an aqueoussolubility of ≦5 mg/ml. Such insoluble drugs include, for example,acetaminophen (APAP), naproxen, theophylline, nifedipine andindomethacin.

In the present invention, the insoluble drug(s) is incorporated into atablet core which is designed to provide immediate dissolution of thedrug upon exposure of the tablet core to aqueous solutions, including invitro dissolution solutions and gastrointestinal fluid.

In certain preferred embodiments of the present invention, the immediaterelease tablet core is obtained by mixing the required quantity ofinsoluble drug having a necessary particle size with other materialsusually included in tablets, such as diluents, lubricants, binders, etc.In certain embodiments, for example, it may be necessary to include oneor more disintegrants in the tablet core. After the insoluble drug ismixed with the additional tableting ingredients, the mixture is thentableted on a suitable tableting machine.

The resultant immediate release tablet core should meet the dissolutionrequirements for immediate release tablets of the therapeutically activeagent as set forth in USP XXII. For example, when the insoluble drug isacetaminophen, the tablet core preferably dissolves in 900 ml of pH 5.8phosphate buffer in 30 minutes.

The immediate release tablet cores containing the insoluble drug(s) arepreferably film coated with a material that permits release of theinsoluble drug at a controlled rate in an aqueous medium. The film coatis preferably chosen so as to achieve, in combination with the otheringredients, an in vitro dissolution rate for a 12 or 24-hour dosageform, when measured by the USP Paddle Method at 100 rpm in 900 mlaqueous buffer, substantially independent of pH, at 37° C. between 12.5and 42.5% (by wt) drug released after 1 hour, between 25 and 56% (by wt)drug released after 2 hours, between 45 and 75% (by wt) drug releasedafter 4 hours and between 55 and 85% (by wt) drug released after 6hours. USP Paddle Method is the Paddle Method described, e.g., in U.S.Pharmacopoeia XXII (1990).

In the present specification, "substantially independent of pH" meansthat the difference, at any given time, between the amount of drugreleased at, e.g., pH 1.6, and the amount released at any other pH,e.g., pH 7.2 (when measured in vitro using the USP Paddle Method at 100rpm in 900 ml aqueous buffer), is 10% (by weight) or less, the amountsreleased being, in all cases, a mean of at least three experiments.

The film coat will generally include a water insoluble material such asa wax or a wax-like substance, fatty alcohols, shellac, zein,hydrogenated vegetable oils, water insoluble celluloses, polymers ofacrylic and/or methacrylic acid, and any other slowly digestible ordispersible solids known in the art. The coating formulations of thepresent invention should be capable of producing a strong, continuousfilm that is smooth and elegant, capable of supporting pigments andother coating additives, nontoxic, inert, and tack-free. Generally, thefilm coat is applied to the tablet core to achieve a weight gain levelfrom about 2 to about 25 percent. However, the film coat may be lesseror greater depending upon the physical properties of the insolubledrug(s) included in the formulation and the desired release rate. Thesolvent for the hydrophobic coating material may be organic or aqueous.

In a preferred embodiment, the film coating of the present invention isobtained via the use of an aqueous dispersion of a hydrophobic polymer.Preferably, the hydrophobic polymer is selected from (i) a waterinsoluble cellulosic polymer, such as an alkylcellulose, preferablyethylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof; andcured at conditions of temperature and relative humidity greater thanambient conditions until a stabilized dissolution profile substantiallyunaffected by exposure to accelerated storage conditions is obtained. Bythe phrase "accelerated storage conditions" it is meant, e.g., storageconditions of elevated temperature and/or elevated relative humidity.For the purposes of the present invention, "accelerated storageconditions" is defined as storage conditions to which the final drugformulation is subjected for the purpose of obtaining regulatoryapproval (e.g., FDA approval in the U.S.) and an expiration date.

For example, a generally accepted test employed in FDA guidelinesrelates to the storage of a drug product (e.g., in its container andpackage) at 75% Relative Humidity (RH) at 40° C. If the product holds upfor, e.g., three months under these conditions (chemical stability,dissolution, and physical characteristics), then the drug product willbe accorded, e.g., a two year expiration date. Other generally acceptedaccelerated tests include those where the drug product is subjected to80% RH and 37° C. for, e.g., one month or longer, and preferably threemonths.

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is an acrylicpolymer. Any acrylic polymer which is pharmaceutically acceptable can beused for the purposes of the present invention. The acrylic polymers maybe cationic, anionic or non-ionic polymers and may be acrylates,methacrylates, formed of methacrylic acid or methacrylic acid esters.These polymers can be synthesized, as indicated above, to be cationic,anionic or non-ionic, which then renders the polymers that would be pHdependent and consequently soluble in, or resistant to solutions over awide range in pH. The most available of the acrylic polymers for thepurposes of the present invention are those that are marketed under thetrade name "EUDRAGIT" and are available from Rohm Pharma. GmbH,Weiterstat, West Germany.

Examples of suitable acrylic polymers include but are not limited toacrylic acid and methacrylic acid copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cynaoethyl methacrylate, methyl methacrylate, copolymers, methacrylicacid copolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methyl methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. This list is not meant to beexclusive.

Preferably, the acrylic polymer is comprised of one or more ammoniomethacrylate copolymers. Ammonio methacrylate copolymers are well knownin the art, and are described in NF XVII as fully polymerized copolymersof acrylic and methacrylic acid esters with a low content of quaternaryammonium groups. In order to obtain a desirable dissolution profile fora given therapeutically active agent, such as that detailed above, itmay be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties. For example, it isknown that by changing the molar ratio of the quaternary ammonium groupsto the neutral (meth)acrylic esters, the permeability properties of theresultant coating can be modified.

The inclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic polymer will further improve the physicalproperties of the film. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is necessary to plasticize theethylcellulose before using the same as a coating material.

The plasticization of the ethylcellulose may be accomplished either byso-called "internal plasticization" and "external plasticization." Thesuitability of a plasticizer depends on its affinity or solvating powerfor the polymer and its effectiveness at interfering withpolymer-polymer attachments. Such activity imparts the desiredflexibility by relieving molecular rigidity. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentration of the plasticizer, however,can only be properly determined after careful experimentation with theparticular coating solution and method of application. Most preferably,about 20% plasticizer is included in the aqueous dispersion of acrylicpolymer.

An important parameter in the determination of a suitable plasticizerfor a polymer is related to the glass transition temperature (Tg) of thepolymer. The glass transition temperature is related to the temperatureor temperature range where there is a fundamental change in the physicalproperties of the polymer. This change does not reflect a change instate, but rather a change in the macromolecular mobility of thepolymer.

Below the Tg, the polymer chain mobility is severely restricted. Thus,for a given polymer, if its Tg is above room temperature, the polymerwill behave as a glass, being hard, non-pliable and rather brittle,properties which could be somewhat restrictive in film coating since thecoated dosage form may be subjected to a certain amount of externalstress.

Incorporation of suitable plasticizers into the polymer matrixeffectively reduces the Tg, so that under ambient conditions the filmsare softer, more pliable and often stronger, and thus better able toresist mechanical stress.

Other aspects of suitable plasticizers include the ability of theplasticizer to act as a good "swelling agent" for the ethylcellulose,and the solubility profile of the plasticizer in water.

Examples of suitable plasticizers for ethylcellulose include dibutylsebacate, diethyl phthalate, triethyl citrate and tibutyl citrate,although it is possible that other plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invent on.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

In one preferred embodiment, the acrylic coating is an acrylic resinlacquers used in the form of an aqueous dispersion, such as that whichis commercially available from Rohm Pharma under the TradenameEudragit®. In further preferred embodiments, the acrylic coatingcomprises a mixture of two acrylic resin lacquers commercially availablefrom Rohm Pharma under the Tradenames Eudragit® RL 30 D and Eudragit® RS30 D, respectively. Eudragit® RL 30 D and Eudragit® RS 30 D arecopolymers of acrylic and methacrylic esters with a low content ofquaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL 30 Dand 1:40 in Eudragit® RS 30 D. The mean molecular weight is about150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a controlledrelease formulation having a desirable dissolution profile. Desirablecontrolled release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL; 50% Eudragit® RL, 50%Eudragit® RS; and 10% Eudragit® RL, 90% Eudragit® RS.

The stabilized controlled release formulations of the present inventionslowly release the insoluble drug(s), e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The controlled releaseprofile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the aqueousdispersion of hydrophobic polymer, altering the manner in which theplasticizer is added to the aqueous dispersion of hydrophobic polymer,by varying the amount of plasticizer relative to hydrophobic polymer, bythe inclusion of additional ingredients or excipients, by altering themethod of manufacture, etc.

The coating solutions of the present invention may contain, in additionto the film-former, plasticizer, and solvent system (i.e., preferablywater but also encompassing organic solvents), a colorant to provideelegance and product distinction. Color may be added to the solution ofthe therapeutically active agent instead, or in addition to the aqueousdispersion of hydrophobic polymer. For example, color can be added toAquacoat® via the use of alcohol or propylene glycol based colordispersions, milled aluminum lakes and opacifiers such as titaniumdioxide by adding color with shear to the water soluble polymer solutionand then using low shear to the plasticized Aquacoat®. Alternatively,any suitable method of providing color to the formulations of thepresent invention may be used. Suitable ingredients for providing colorto the formulation when an aqueous dispersion of an acrylic polymer isused include titanium dioxide and color pigments, such as iron oxidepigments.

The plasticized aqueous dispersion of hydrophobic polymer may be appliedonto the tablet core comprising the insoluble drug by spraying, usingany suitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of theaqueous dispersion of hydrophobic polymer to obtain a predeterminedcontrolled release of the therapeutically active agent when the coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, ispreferably applied, taking into account the physical characteristics ofthe therapeutically active agent, the manner of incorporation of theplasticizer, etc. After coating with the hydrophobic polymer, a furtherovercoat of a film-former, such as hydroxypropylmethylcellulose (e.g.,Opadry®), is optionally applied to the tablets. This overcoat isprovided, if at all, in order to substantially reduce agglomeration ofthe tablets.

Next, the coated tablets are cured in order to obtain a stabilizedrelease rate of the therapeutically active agent.

To date, attempts to prepare stable controlled release pharmaceuticalformulations using aqueous dispersions of hydrophobic polymers have beenunsuccessful due to stability problems. In particular, when coatingthese pharmaceutical forms using aqueous polymeric dispersions to obtaina desired release profile of the active drug(s) over several hours orlonger, it is known in the art that the dissolution release profilechanges on ageing.

This problem has been overcome by curing the coated tablet at atemperature greater than the glass transition temperature of the aqueousdispersion of plasticized hydrophobic polymer and at a necessaryrelative humidity until an endpoint is reached at which said substrateattains a dissolution profile which is substantially unaffected byexposure to accelerated storage conditions, e.g., of about 37°-40° C.and about 75-80% relative humidity for three months or longer. In otherwords, the cured coated tablet will provide a stable dissolution profilewhen comparing the in vitro dissolution of the therapeutically activeagent immediately after curing to the in vitro dissolution of thetherapeutically active agent after exposing the cured coated substrateto accelerated conditions of three months at from about 37° C. to about40° C. and from about 75% to about 80% pH. By "stable" it is meant thatthe in vitro dissolution falls within acceptable limits in comparison tothe dissolution profile of the coated cured substrate immediately aftercuring, the acceptable limits being determined by a regulatory agencysuch as the U.S. F.D.A.

In the embodiment of the present invention wherein an aqueous dispersionof ethylcellulose is used as the controlled release coating, wherein thecuring step is accomplished by subjecting the coated substrate togreater than normal, ambient (i.e., room) temperature and relativehumidity and continuing the curing until an endpoint is reached at whichthe coated beads attain a dissolution profile which is substantiallyunaffected by further exposure to storage conditions of elevatedtemperature and/or humidity. More particularly, the coated substrates ofthe present invention should be cured at a temperature greater than theglass transition temperature of the coating solution (i.e.,ethylcellulose) and at a greater than ambient humidity.

In preferred embodiments of the present invention, the stabilizedproduct derived from an aqueous dispersion of ethylcellulose is obtainedby subjecting the coated substrate to oven curing at the aforementionedtemperature/humidity levels for the required time period, the optimumvalues for temperature, humidity and time for the particular formulationbeing determined experimentally. In certain preferred embodiments, thestabilized product coated with an aqueous dispersion of ethylcelluloseis obtained via an oven curing conducted at a temperature of about 60°C. and a relative humidity from about 60% to about 100% for a timeperiod from about 48 to about 72 hours.

Traditionally, curing has been carried out for Eudragit® coatedformulations, if at all, via a fluid bed at 45° C. for 2 hours afterapplication. Such a standard curing is recommended by Rohm Pharmabecause it is above the glass transition temperature (Tg) of Eudragit®RS 30 D plasticized with triethylcitrate at a 20% level of solids.However, this recommended curing does not stabilize the dissolutionprofile of the formulation upon exposure to accelerated storageconditions.

This problem is overcome in the embodiment of the present inventionwherein the aqueous dispersion of hydrophobic polymer comprises anaqueous dispersion of an acrylic polymer such as Eudragit®, wherein thestabilized product is obtained via an oven curing conducted at atemperature greater than the Tg of the coating formulation andcontinuing the curing until an endpoint is reached at which the coatedformulation. In other words, the cured coated tablet will provide astable dissolution profile when comparing the in vitro dissolution ofthe therapeutically active agent immediately after curing to the invitro dissolution of the therapeutically active agent after exposing thecured coated substrate to accelerated conditions of three months at fromabout 37° C. to about 40° C. and from about 75% to about 80% RH. By"stable" it is meant that the in vitro dissolution falls withinacceptable limits in comparison to the dissolution profile of the coatedcured substrate immediately after curing. The acceptable limits beingdetermined by a regulatory agency such as the U.S. F.D.A.

In preferred embodiments of the present invention directed to theacrylic coating, the stabilized product is obtained by subjecting thecoated substrate to oven curing at a temperature above the Tg of theplasticized acrylic polymer for the required time period, the optimumvalues for temperature and time for the particular formulation beingdetermined experimentally. In certain embodiments of the presentinvention, the stabilized product is obtained via an oven curingconducted at a temperature of about 45° C. for a time period from about24 to about 48 hours. It is also contemplated that certain productscoated with the controlled release coating of the present invention mayrequire a curing time longer than 48 hours, e.g. 60 hours or more.

One skilled in the art will recognize that necessary curing conditionswill vary, depending upon (among other things) the particulartherapeutically active agent included in the formulation, the size ofthe substrate, the thickness of the coating, the percentage ofhydrophobic polymer included in the aqueous dispersion, the presence andamount of additional rate-controlling agents included in the aqueousdispersion of hydrophobic polymer. The necessary time period to cure tothe stabilized end point may also be affected by the above variants andothers. Such curing conditions are contemplated to be within the scopeof the present invention and the appended claims.

The release of the therapeutically active agent from the controlledrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents included in the coating. The amount of suchrelease-modifying agents included in the coating will depend upon therelease rate required and the solubility characteristics of the agentselected, among other things.

For example, the controlled release coating may comprise a water solublematerial(s) in addition to the hydrophobic polymer. The ratio ofhydrophobic polymer to water soluble material is determined by, amongother factors, the release rate required and the solubilitycharacteristics of the materials selected. Suitable water solublematerials include hydrophilic polymers.

Also, cellulose ethers and protein-derived materials can be included inthe controlled release coating to modify the release characteristicsthereof. These materials include, but are not limited to cellulosederivatives, including but not limited to hydroxyalkyl celluloses andcarboxyalkyl celluloses, such as hydroxypropyl-cellulose,hydroxypropylmethylcellulose, methoxypropyl cellulose, hydroxyethylcellulose, and other derivatives known to those skilled in the art. Eachof these cellulosic derivatives are available in a range of molecularweights and viscosities, etc., and the particular cellulosic derivativeto be utilized in the present invention may be chosen as the needarises. Semipermeable polymers may also be used. Such polymers include,for example, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, beta-glycan acetate, acetaldehyde dimethyl acetate,cellulose acetate ethyl carbamate, polyamide, polyurethane, sulfonatedpolystyrene, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetatedimethylaminoacetate, cellulose acetate chloracetate, cellulosedipalmitate, cellulose dioctanoate, cellulose dicaprylate, cellulosedipentanlate, cellulose acetate valerate, cellulose acetatep-toluenesulfonate, cellulose acetate butyrate, and other semipermeablepolymers such as those described in U.S. Pat. No. 4,285,987 (herebyincorporated by reference), selectively permeable polymers formed by thecoprecipitation of a polycation and a polyanion as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142(hereby incorporated by reference).

In addition, a water-soluble polydextrose may be used. A water-solublepolydextrose is defined for the purposes of the present invention as apolydextrose that dissolves to a level of at least about 1% (W/W) inwater at 25° C. Also, synthetic water-soluble polymers may be used, suchas polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethyleneoxide, etc., and polysaccharides, e.g., pullulan, dextran, etc.

The controlled release coatings of the present invention can alsoinclude release-modifying agents such as cellulose acetate phthalate,such as those disclosed in U.S. Pat. No. 2,196,768, herein incorporatedby reference. Other suitable release-controlling agents which may beincluded in the controlled release coating of the present inventioninclude shellac, zein, hydroxypropylmethyl cellulose phthalate,sandarac, modified shellac, etc.

The release-modifying agents of the present invention also encompasserosion-promoting agents such as starch (including, but not limited tocorn starch, rice starch, a starch, carboxymethyl starch, potato starch,and other vegetable starches), modified starch, and starch derivatives.This category is also intended to include other erosion-promoting agentssuch as gums (e.g., xanthan gum, alginic acid, other alginates,bentonite, veegum, agar, guar, locust bean gum, gum arabic, quincepsyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth,scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambdacarrageenan, gumkaraya, biosynthetic gum, etc.).

The controlled release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use. Materials useful for making the microporous laminainclude polycarbonates comprised of linear polyesters of carbonic acidin which carbonate groups reoccur in the polymer chain, microporousmaterials prepared by the phosgenation of a dihydroxyl aromatic such asbisphenol, a microporous poly(vinylchloride), microporous polyamidessuch as polyhexamethylene adipamide, microporous modacrylic copolymersincluding those formed from poly(vinychloride) and acrylonitrile,microporous styreneacrylic and its copolymers, porous polysulfonescharacterized by diphenylene sulfone in a linear chain thereof,halogenated poly(vinylidene), polychloroethers, acetal polymers,polyesters prepared by esterification of a dicarboxylic acid oranhydride with an alkylene polyol, poly(alkylenesulfides), phenolics,polyesters, microporous polysaccharides having substitutedanhydroglucose units exhibiting a decreased permeability to the passageof water and biological fluids, asymmetric porous polymers, cross-linkedolefin polymers, hydrophobic or hydrophilic microporous homopolymers,copolymers or interpolymers having a reduced bulk density, and materialsdescribed in U.S. Pat. Nos. 3,595,752; 3,643,178; 3,654,066; 3,709,774;3,718,532; 3,803,601; 3,852,224; 3,852,388; and 3,853,601 (all of whichare hereby incorporated by reference); in British Pat. No. 1,126,849;and in Chem. Abst. Vol. 71, 427F, 22573F, 1969.

Additional microporous materials for forming microporous lamina includepoly(urethane), cross-linked chain-extended poly(urethane),poly(imides), poly(benzimidazole), collodion, regenerated proteins,semi-solid cross-linked poly(vinylpyrrolidone), microporous materialsprepared by diffusion of multivalent cations into polyelectrolyte sols,microporous derivatives of poly(styrene) such aspoly(sodium-styrenesulfonate), poly(vinyl benzyl trimethyl-ammoniumchloride), microporous cellulosic acrylates and the like microporouspolymers such as those described in U.S. Pat. Nos. 3,524,753; 3,565,259;3,276,589; 3,541,055; 3,541,006; 3,546,142; 3,615,024; 3,646,178, and3,852,224 (all of which are hereby incorporated by reference).Pore-formers useful for forming the microporous lamina in theenvironment of use include solids and pore-forming liquids.

The term pore-former as used herein also embraces micropath formers, andremoval of the pore and/or pore-former leads to both embodiments. In theexpression pore-forming liquids, the term for this invention genericallyembraces semi-solids and viscus fluids. The pore-formers can beinorganic or organic. The term pore-former for both solids and liquidsinclude substances that can be dissolved, extracted or leached from theprecursor microporous wall by fluid present in the environment of use toform open-celled type microporous lamina. The pore-forming solids have asize, e.g., of about 0.1 to 200 microns and they include alkali metalsalts such as lithium carbonate, sodium chloride, sodium bromide,potassium chloride, potassium sulfate, potassium phosphate, sodiumacetate, sodium citrate, suitable calcium salts, and the like. Organiccompounds such as polysaccharides including the sugars sucrose, glucose,fructose, mannitol, mannose, galactose, sorbitol and the like. They canbe polymers soluble in the environment of use such as Carbowaxes®,Carbopol®, and the like. The pore-formers embrace diols, polyols,polyhydric alcohols, polyalkylene glycols, polyglycols,poly(a-w)alkylenediols, and the like. The pore-formers are non-toxic andon their removal from lamina, channels and pores are formed through thelamina that fill with fluid present in the environment use.

The controlled release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

In addition to the inclusion of one or more drugs having a aqueoussolubility of less than or equal to about 5 mg/ml, the controlledrelease formulations of the present invention can also include one ormore drugs which are highly soluble in water relative to the insolubledrug. These relatively soluble drugs can be incorporated into theimmediate release tablet core. The rate of release for such solubledrugs will depend upon the sustained release film coat, and is notdependent upon the core being rapidly dissolvable and/ordisintegratable. Examples of such relatively soluble drugs which may beincluded in the controlled release formulations of the present inventioninclude antihistamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.),non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac,ibuprofen, aspirin, sulindac), gastrointestinals and anti-emetics (e.g.,metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate andnitrezepam), vasodilators (e.g., papaverine, diltiazem), cholinergics(e.g., neostigmine, pyridostigmine), anti-tussive agents andexpectorants (e.g., codeine phosphate), antituberculosis agents (e.g.,isoniazid), anti-spasmodics (e.g. atropine, scopolamine),anti-muscarinics (e.g., anisotropine), hormones (e.g., insulin,heparin), diuretics (e.g., bendrofluazide), anti-hypotensives (e.g.,propranolol, clonidine), bronchodilators (e.g., albuterol), ironpreparations (e.g, ferrous gluconate), anti-inflammatory steroids (e.g.,hydrocortisone, triamcinolone, prednisone), antibiotics (e.g.,penicillin V, tetracycline, clindamycin, novobiocin, metronidazde,cloxacillin), antihemorrhoidals, antidiarrheals, mucolytics, sedatives,decongestants, laxatives, antacids, vitamins (e.g., ascorbic acid),sympathomimetics (e.g., ephedrine, phenylpropanolamine). The above listis not meant to be exclusive.

In one preferred embodiment of the invention, the insolubletherapeutically active agent is acetaminophen, and the solubletherapeutically active agent is selected from the group consisting ofhydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine,morphine, buprenorphine, other opioids, salts of any of the foregoing,and mixtures of any of the foregoing.

In certain preferred embodiments of the present invention, the immediaterelease tablet core comprises from about 300 mg to about 500 mgacetaminophen and from about 5 to about 10 mg oxycodone, and preferablyabout 325 mg acetaminophen and about 10 mg oxycodone. In other preferredembodiments, the formulations of the present invention include formabout 300 mg to about 500 mg (and preferably about 450 mg) acetaminophentogether with from about 15 mg to about 60 mg (and preferably about 45mg) codeine phosphate. In such embodiments, the tablet core will allowthe dissolution of not less than 75% of the labeled amounts ofacetaminophen and codeine phosphate hemihydrate when the tablet coreplaced in 900 ml 0.1 N hydrochloric acid for 45 minutes, as set forth inUSP XXII. The amount of drug dissolved is determined using the assaymethod set forth in the Official Monograph for acetaminophen and codeinephosphate tablets set forth in USP XXII.

Immediate release APAP tablets or tablet cores may be prepared by wetgranulating acetaminophen powder with a binder, then drying and sievingthe resultant granules. Thereafter, a suitable adjuvant and lubricantare added and mixed. The mixture is then compressed.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Immediated Release APAP Cores Overcoated With ControlledRelease Coating

Immediate release APAP tablets are prepared by mixing the Acetaminophenpowder with polyvinylpyrrolidone for 5 minutes in a Collette mixer. Thenthe powders are granulated using an appropriate amount of purifiedwater.

After the batch is granulated, the wet granulation is dried in a fluidbed dryer at 60° C. inlet air temperature until the granulation issufficiently dry for screening. When the granulation is sufficientlydry, it is passed through a Comil using a suitable screen size. Thegranulation is then placed in a V-Blender, the lactose is then added andmixed. The tablets are compressed to a weight of about 664.5 mg pertablet.

The coating suspension is prepared by dispersing Methocel E5 premium(commercially available from, e.g., Dow Chemical Co., St. Louis, Mo.) in3 times its weight of boiling purified water while mixing for about10-20 minutes. Thereafter, sufficient purified water at ambienttemperature is added to the mixture such that the final concentration ofthe coating suspension is about 20% w/w. The coating suspension is mixedfor about one to one and one-half hours until the methocel(hydroxypropylmethylcellulose) is completely dispersed. Then themethocel dispersion is cooled while mixing to a temperature below about40° C.

In a separate container, a plasticizer (i.e., triethyl citrate) is mixedwith Aquacoat ECD-30 suspension for about 15 minutes. Then, the AquacoatECD-30 dispersion is added to the Methocel dispersion and mixed forabout 15 minutes to insure a thorough mixing. Afterwards, water isadded, if necessary, to replace any water which had been lost byevaporation.

The immediate release tablets are then coated in an Accela Cota Panusing an appropriate spray gun and fittings. The spraying is continueduntil the tablets attain the required weight gain (in Example 1, to aweight gain of about 5%; in Example 2, to a weight gain of about 10%),by periodically weighing a small sample during the coating process. Thecoated tablets are cured in a curing oven at 60° C./80% RH for a minimumof about 3 days.

The final composition of the Tablets of Examples 1-2 are set forth inTables 1 and 2 below, respectively.

                  TABLE 1                                                         ______________________________________                                        EXAMPLE 1 - APAP IMMEDIATE RELEASE                                            TABLETS OVERCOATED TO A 5% WEIGHT GAIN                                        Theoretical                                                                   Amt/Tablet (mg)                                                                            Ingredients                                                      ______________________________________                                        500          Acetaminophen powder                                             40           PVP                                                              123          Lactose, Hydrogen, spray dried                                   1.5          Magnesium stearate                                               16.6 (of solids)                                                                           Aquacoat ECD-30 (as a 30% w/w suspension)                        16.6         Methocel E5 premium                                              6.6          Triethyl citrate (PG)                                            q.s.         Purified water                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        EXAMPLE 2 - APAP IMMEDIATE RELEASE                                            TABLETS OVERCOATED TO A 10% WEIGHT GAIN                                       Theoretical                                                                   Amt/tab. (mg)                                                                             Ingredients                                                       ______________________________________                                        500         Acetaminophen powder                                              40          PVP                                                               123         Lactose, Hydrogen, spray dried                                    1.5         Magnesium stearate                                                33.2        Aquacoat ECD-30 (As a 30% w/w suspension)                         33.2        Methocel E5 premium                                               13.3        Triethyl citrate (PG)                                             q.s.        Purified water                                                    ______________________________________                                    

Next, tablets of Examples 1 and 2 are subjected to dissolution testing.The dissolution testing is carried out via the USP Basket Method, 37°C., 100 RPM, as previously described. The mean tablet weights ofExamples 1 and 2 were 716 mg and 756.7 mg, respectively. The results areset forth in Tables 3-4 below, respectively.

                  TABLE 3                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 1                                              APAP 500 MG TABLETS WITH CONTROLLED                                           RELEASE AQUACOAT/METHOCOL 50:50 COATING                                       TO A 5% WT GAIN CURED 3 DAYS AT 60° C./80% RH                                      Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           5.4                                                               2           11.8                                                              4           22.2                                                              8           41.8                                                              12          60.0                                                              18          82.0                                                              24          98.3                                                              ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 2                                              APAP 500 MG TABLETS WITH CONTROLLED                                           RELEASE AQUACOAT/METHOCOL 50:50 COATING                                       TO A 10% WT GAIN CURED 3 DAYS AT 60° C./80% RH                                     Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           2.7                                                               2           6.6                                                               4           14.0                                                              8           27.2                                                              12          40.2                                                              18          57.8                                                              24          73.6                                                              ______________________________________                                    

EXAMPLES 3-4 Reproducibility of Dissolution Result--Immediate ReleaseAPAP Cores Overcoated With Controlled Release Coating Using Same Lot ofAcetaminophen Powder

In order to determine whether the dissolution profiles obtained frombatch-to-batch would be acceptably similar when using the same lot ofacetaminophen powder raw material or a different lot of the same gradeof acetaminophen powder or further still a different grade ofacetaminophen powder with a smaller particle size, the followingexamples were prepared:

In Examples 3 and 4, using the same lot of APAP powder, new batches ofthe tablets of Examples 1-2 (immediate release APAP tablets overcoatedwith controlled release coating) are made in order to determine whetherthe dissolution profiles obtained from batch-to-batch and using the samelot of acetaminophen powder would be acceptable. The tablets aremanufactured, coated and cured in the same manner as set forth abovewith respect to Examples 1-2. The tablets of Example 3 are coated to aweight gain of about 5% (mean tablet weight 712.7 mg), whereas thetablets of Example 4 are coated to a weight gain of about 10% (meantablet weight 757.6 mg). Thereafter, dissolution testing via the sameUSP Basket Method, 37° C., 100 RPM, as previously described, wasconducted. The results are set forth in Tables 5-6 below, respectively.

                  TABLE 5                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 3 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCOL 50:50 COATING TO A 5% WT GAIN                               CURED 3 DAYS USING SAME LOT ACETAMINOPHEN POWDER                              AS IN EXAMPLE 1 AT 60° C./80% RH                                                   Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           8.5                                                               2           14.0                                                              4           23.5                                                              8           41.3                                                              12          58.2                                                              18          80.6                                                              24          99.8                                                              ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 4 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCOL 50:50 COATING TO A 10% WT GAIN                              CURED 3 DAYS USING SAME LOT ACETAMINOPHEN POWDER                              AS IN EXAMPLE 2 AT 60° C./80% RH                                                   Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           3.9                                                               2           7.8                                                               4           16.0                                                              8           30.2                                                              12          43.8                                                              18          62.6                                                              24          77.1                                                              ______________________________________                                    

The dissolution profiles of the tablets of Example 3 proved to besubstantially similar to the dissolution profiles of the tablets ofExample 1. Likewise, the dissolution profiles of the tablets of Example4 proved to be substantially similar to the dissolution profiles of thetablets of Example 2. The results indicate that the batch-to-batchvariation with respect to dissolution and using the same lot ofacetaminophen powder would be acceptable when developing a controlledrelease product of a relatively insoluble drug for commercial use, e.g.,to governmental regulatory authorities such as the United States Foodand Drug Administration (F.D.A.).

EXAMPLES 5-6 Reproducibility of Dissolution Results--Immediate ReleaseAPAP Cores Overcoated with Controlled Release Coating using a DifferentLot of Acetaminophen Powder

In Examples 5 and 6, new batches are made of the tablets of Examples 1-2(immediate release APAP tablets overcoated with controlled releasecoating) in order to determine whether the dissolution profiles obtainedfrom batch to batch and using a different lot of acetaminophen powder,would be acceptably similar. The tablets are manufactured, coated andcured in the same manner as set forth above with respect to Examples1-2. The tablets of Example 5 are coated to a weight gain of about 5%(mean tablet weight 711.3 mg), whereas the tablets of Example 6 arecoated to a weight gain of about 10% (mean tablet weight 745.8 mg).Thereafter, dissolution testing via the same USP Basket Method, 37° C.,100 RPM, as previously described, was conducted. The results are setforth in Tables 7-8 below, respectively.

                  TABLE 7                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 5 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCEL 50:50 COATING TO A 5% WEIGHT GAIN                           CURED 3 DAYS AT 60° C./80% RH USING A DIFFERENT LOT OF                 ACETAMINOPHEN POWDER                                                                      Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           6.5                                                               2           13.1                                                              4           23.7                                                              8           43.9                                                              12          61.4                                                              18          82.9                                                              24          100.0                                                             ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 6 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCEL 50:50 COATING TO A 10% WEIGHT GAIN                          CURED 3 DAYS AT 60° C./80% RH USING A DIFFERENT LOT OF                 ACETAMINOPHEN POWDER                                                                      Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           3.3                                                               2           7.5                                                               4           15.5                                                              8           29.3                                                              12          42.5                                                              18          60.9                                                              24          77.1                                                              ______________________________________                                    

The dissolution profiles of the tablets of Example 5 proved to besubstantially similar to the dissolution profile of the tablets ofExample 1. Likewise, the dissolution profiles of the tablets of Example6 proved to be substantially similar to the dissolution profiles of thetablets of Example 2.

The results indicate that the batch-to-batch variation with respect todissolution and using a different lot of acetaminophen powder would beacceptable when developing a controlled release product, thus indicatingthat such a product is reproducible and would meet FDA requirements.

EXAMPLES 7-8 Reproducibility of Dissolution Results--Immediate ReleaseAPAP Cores Overcoated with Controlled Release Coating UsingAcetaminophen Powder of a Finer Particle Size

In Examples 7 and 8, new batches are made of the tablets of Examples 1-2(immediate release APAP tablets overcoated with controlled releasecoating) in order to determine whether the dissolution profiles obtainedusing a finer particle size acetaminophen powder, would be acceptablysimilar to the dissolution profiles of Examples 1 and 2. The tablets aremanufactured, coated and cured in the same manner as set forth abovewith respect to Examples 1-2. The tablets of Example 7 are coated to aweight gain of about 5% (mean tablet weight 711.5 mg), whereas thetablets of Example 8 are coated to a weight gain of about 10% (meantablet weight 751.7 mg). Thereafter, dissolution testing via the sameUSP Basket Method, 37° C., 100 RPM, as previously described wasconducted. The results are set forth in Tables 9-10 below, respectively.

                  TABLE 9                                                         ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 7 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCEL 50:50 COATING TO A 5% WEIGHT GAIN                           CURED 3 DAYS AT 60° C./80% RH USING ACETAMINOPHEN                      POWDER OF A FINER PARTICLE SIZE                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           7.1                                                               2           13.4                                                              4           24.3                                                              8           44.8                                                              12          63.8                                                              18          87.9                                                              24          103.7                                                             ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 8 - APAP 500 MG                                TABLETS WITH CONTROLLED RELEASE                                               AQUACOAT/METHOCEL 50:50 COATING TO A 10%                                      WEIGHT GAIN CURED 3 DAYS AT                                                   60° C./80% rh USING ACETAMINOPHEN POWDER OF A                          FINER PARTICLE SIZE                                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                         1          3.5                                                                2          8.0                                                                4          15.6                                                               8          29.4                                                              12          43.0                                                              18          61.6                                                              24          76.0                                                              ______________________________________                                    

The dissolution profiles of the tablets of Example 7 proved to besubstantially similar to the dissolution profiles of the tablets ofExample 1. Likewise, the dissolution profiles of the tablets of Example8 proved to be substantially similar to the dissolution profiles of thetablets of Example 2.

The results indicate that variation with respect to dissolution using adifferent (finer) particle size acetaminophen powder would be acceptablewhen developing a controlled release product, which is a surprisingfinding for water-insoluble drugs. The data for all of the examples forthe 5% controlled release coatings are also represented graphically inFIG. 1. From FIG. 1, it can be observed that the dissolution fromExamples 1, 3, 5 and 7 are virtually superimposible. Thus showingexcellent reproducibility from one batch to a second batch with the sameraw material or a different lot of raw material, or even another lot ofraw material of different particle size. Similarly, the results for the10% controlled release coatings of the tablets from Examples 2, 4, 6 and8 are shown in FIG. 2.

EXAMPLES 9-10 Reproducibility of Dissolution Results Immediate ReleaseCodeine/APAP Cores Overcoated with Controlled Release Coating

In order to determine whether the dissolution profiles obtained would beacceptably similar if a second active ingredient was incorporated in theimmediate release core, Examples 9 and 10, were prepared, wherein newbatches are made of the tablets of Examples 1-2 (immediate release APAPtablets overcoated with controlled release coating), but with theexception of incorporating codeine base in the powder mixture withacetaminophen and polyvinylpyrrolidone prior to the 5 minute dry mix.Codeine phosphate is a relatively soluble drug in comparison to APAP.

The tablets are manufactured, coated and cured in the same manner as setforth above with respect to Examples 1-2. The tablets of Example 9 arecoated to a weight gain of about 5% (mean tablet weight 758.6 mg),whereas the tablets of Example 10 are coated to a weight gain of about10% (mean tablet weight 799.4 mg). Thereafter dissolution testing viathe same USP Basket Method, 37° C., 100 RPM, as previously described wasconducted.

The final composition of the tablets of Examples 9-10 are set forth inTables 11-12 below. The dissolution results for Example 9 are set forthin Tables 13-14 below, and the dissolution results for Example 10 areset forth in Tables 15 and 16 below (dissolution reported separately forAPAP and codeine).

                  TABLE 11                                                        ______________________________________                                        EXAMPLE 9 - CODEINE/APAP IMMEDIATE                                            RELEASE TABLETS OVERCOATED TO A 5% WEIGHT GAIN                                Theoretical                                                                   Amt/Tablet (mg)  Ingredient                                                   ______________________________________                                        35.94                codeine base, monohydrate                                500                  Acetaminophen powder                                     40                   PVP                                                      123                  Lactose, Hydrous, spray dried                            1.5                  Magnesium stearate                                       17.51    (of solids) Aquacoat ECD-30                                                               (as a 30% w/w suspension)                                17.51                Methocel E5 premium                                      7.00                 Triethyl citrate (PG)                                    q.s.                 purified water                                           742.46   (Total)                                                              ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                        EXAMPLE 10 - CODEINE/APAP IMMEDIATE                                           RELEASE TABLETS OVERCOATED TO A 10% WEIGHT GAIN                               Theoretical                                                                   Amt/Tablet (mg)  Ingredient                                                   ______________________________________                                        35.94                codeine base, monohydrate                                500                  Acetaminophen powder                                     40                   PVP                                                      123                  Lactose, Hydrous, Spray dried                            1.5                  Magnesium stearate                                       35.02    (of solids) Aquacoat ECD-30                                                               (as a 30% W/W suspension)                                35.02                Methocel E5 premium                                      14.01                Triethyl citrate (PG)                                    q.s.                 purified water                                           784.49   (Total)                                                              ______________________________________                                    

                  TABLE 13                                                        ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 9 - APAP                                       500 MG TABLETS WITH CONTROLLED RELEASE                                        AQUACOAT/METHOCEL 50:50 COATING TO A 5%                                       WEIGHT GAIN CURED 3 DAYS AT 60° C./80% RH                              PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           10.0                                                              2           13.5                                                              4           23.7                                                              8           41.8                                                              12          57.8                                                              18          76.4                                                              24          91.4                                                              ______________________________________                                    

                  TABLE 14                                                        ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 9 - APAP                                       500 MG TABLETS WITH CONTROLLED RELEASE                                        AQUACOAT/METHOCEL 50:50 COATING TO A 5%                                       WEIGHT GAIN CURED 3 DAYS AT 60° C./80% RH                              PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           17.1                                                              2           26.3                                                              4           40.2                                                              8           60.7                                                              12          76.3                                                              18          92.0                                                              24          101.1                                                             ______________________________________                                    

                  TABLE 15                                                        ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 10 - APAP                                      500 MG TABLETS WITH CONTROLLED RELEASE                                        AQUACOAT/METHOCEL 50:50 COATING TO A 10%                                      WEIGHT GAIN CURED 3 DAYS AT 60° C./80% RH                              PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           3.6                                                               2           8.0                                                               4           16.6                                                              8           31.6                                                              12          45.9                                                              18          64.3                                                              24          79.1                                                              ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                        DISSOLUTION RESULTS OF EXAMPLE 10 - APAP                                      500 MG TABLETS WITH CONTROLLED RELEASE                                        AQUACOAT/METHOCEL 50:50 COATING TO A 10%                                      WEIGHT GAIN CURED 3 DAYS AT 60° C./80% RH                              PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           10.8                                                              2           19.8                                                              4           33.5                                                              8           52.9                                                              12          68.1                                                              18          84.9                                                              24          96.2                                                              ______________________________________                                    

The dissolution profiles of APAP in the tablets of Example 9 proved tobe substantially similar to the dissolution profiles of the tablets ofExamples 1, 3, 5 and 7. Likewise, this data is shown in FIG. 3. APAP inthe tablets of Example 10 proved to be substantially similar to thedissolution profiles of the tablets of Examples 2, 4, 6 and 8. This datais shown in FIG. 4.

The results indicate that the controlled release coating is thecontrolling factor in the dissolution irrespective of the additionaldrug substance content of the core.

COMPARATIVE EXAMPLES 11-12 Controlled Release Matrix Tablets--CodeinePhosphate 45 Mg/APAP 450 Mg

In Comparative Examples 11-12, two separate batches of controlledrelease matrix tablets of codeine phosphate/APAP having identicalformulas and manufacturing techniques are prepared in order to comparethe dissolution profiles of the final product on a batch-to-batch basis.

The final product of Comparative Examples 11 and 12 have the compositionset forth in Table 17 below.

                  TABLE 17                                                        ______________________________________                                        COMPOSITION OF COMPARATIVE EXAMPLES 11-12                                     Amt/tab (mg)    Ingredients                                                   ______________________________________                                         46 mg*         Codeine Phosphate, hemihydrate                                450 mg          Acetaminophen                                                  60 mg          Pregelatinized corn starch                                    120 mg          Cetostearyl alcohol                                            9 mg           Talc                                                           6 mg           Magnesium stearate                                             21 mg          Opadry blue YS-1-4026                                         q.s.            purified water                                                712 mg (Total)                                                                ______________________________________                                         *Equivalent to 45 mg of codeine phosphate, anhydrous.                    

The tablets of Comparative Examples 11-12 are prepared as follows.Codeine Phosphate, APAP and pregelatinized corn starch are mixed forabout 5 minutes in a Collette Mixer. Then, the powders are granulatedusing an appropriate amount of purified water. After the batch isgranulated, the wet granulation is dried in a fluid bed dryer at 60° C.inlet air temperature until granulation is sufficiently dry forscreening. When the granulation is dry enough, it is passed through a #8mesh screen, and then placed in the Collette Mixer.

The required amount of cetostearyl alcohol is melted and then the meltedwax is incorporated into the granulation while mixing for about 1minute. The waxed granulation is cooled to room temperature, and thenpassed through a #12 mesh screen. After screening, the granulation isplaced in the Collette mixer and lubricated with talc and magnesiumstearate. The granulation is then compressed into tablets of theappropriate weight and hardness.

The appropriate amount of film coating suspension is prepared bydispersing Opadry Blue YS-1-4026 in a sufficient amount of purifiedwater, and then film coated in a rotary pan.

The above procedure is followed identically for a separate batch oftablets identified herein as Comparative Example 12.

Tablets of Comparative Example 11 (mean tablet weight 696.6 mg) are thensubjected to dissolution testing. The dissolution testing is carried outseparately with respect to the two drugs in the formulation, codeinephosphate and APAP, in order to determine the rate of in vitro releaseof each of these drugs from the formulation. The dissolution testing iscarried out via the USP Basket Method, 37° C., 100 RPM, as previouslydescribed. The results are set forth in Tables 18 and 19 below.

                  TABLE 18                                                        ______________________________________                                        COMPARATIVE EXAMPLE 11 CODEINE PHOS./APAP                                     45/450 MG CONTROLLED RELEASE MATRIX TABLETS                                   PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           18.0                                                              2           42.5                                                              4           82.2                                                              8           96.8                                                              12          100.1                                                             18          101.2                                                             24          102.0                                                             ______________________________________                                    

                  TABLE 19                                                        ______________________________________                                        COMPARATIVE EXAMPLE 11                                                        CODEINE PHOS./APAP 45/450 MG                                                  CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           37.5                                                              2           69.0                                                              4           99.3                                                              8           101.4                                                             12          101.9                                                             18          102.3                                                             24          103.5                                                             ______________________________________                                    

Dissolution tests were identically carried out for the tablets ofComparative Example 12 (mean tablet weight 714 mg). The results are setforth in Tables 20 and 21 below.

                  TABLE 20                                                        ______________________________________                                        COMPARATIVE EXAMPLE 12                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           14.9                                                              2           29.7                                                              4           63.9                                                              8           89.4                                                              2           94.3                                                              ______________________________________                                    

                  TABLE 21                                                        ______________________________________                                        COMPARATIVE EXAMPLE 12                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           34.0                                                              2           59.4                                                              4           94.8                                                              8           98.4                                                              12          99.4                                                              ______________________________________                                    

The dissolution profiles for codeine phosphate and APAP from theformulation of Comparative Examples 11 and 12 is graphically depicted inFIGS. 5 and 6. As can be readily ascertained, the batch-to-batch invitro dissolution variability for the formulation with respect to therelatively soluble drug, codeine phosphate, was acceptably small.However, the batch-to-batch in vitro dissolution variability for theformulation with respect to the relatively insoluble drug, APAP, wasunacceptably large.

COMPARATIVE EXAMPLES 13-14 Controlled Release Matrix Tablets CodeinePhosphate 45 Mg/APAP 450 Mg

In Comparative Examples 13-14, two separate batches of controlledrelease matrix tablets of codeine phosphate/APAP having identicalformulas and manufacturing techniques are prepared in order to comparethe dissolution profiles of the final product on a batch-to-batch basis.The formulations of Comparative Examples 13-14, while also relying upona controlled release matrix to control the release of the drugs from theformulation, are formulated somewhat differently. The final product ofComparative Examples 13 and 14 have the composition set forth in Table22 below.

                  TABLE 22                                                        ______________________________________                                        COMPOSITION OF COMPARATIVE EXAMPLES 13-14                                     Amt/tab (mg)    Ingredients                                                   ______________________________________                                        46           mg*        Codeine Phosphate, hemihydrate                        450          mg         Acetaminophen                                         60           mg         Pregelatinized corn starch                            4            mg         Acdisol                                               40           mg         Cetostearyl alcohol                                   40           mg         Carbowax 8000                                         9            mg         Talc                                                  3            mg         Magnesium stearate                                    20           mg         Opadry blue YS-1-4026                                 q.s*                    Purified water                                        672          mg (Total)                                                       ______________________________________                                         *Equivalent to 45 mg of codeine phosphate, anhydrous.                    

Comparative Examples 13-14 are prepared as follows. Codeine Phosphate,APAP, Acdisol and pregelatinized corn starch are mixed for about 5minutes in a Collette Mixer. The mixed powders are then granulated usingan appropriate amount of purified water. After the batch is granulated,the wet granulation is dried in a fluid bed dryer until the granulationis sufficiently dry for screening. When the granulation is dry enough,it is passed through a screen and then placed in the Collette Mixer. Therequired amount of cetostearyl alcohol and Carbowax 8000 is melted, andthen the melted wax is incorporated into the granulation while mixing.The waxed granulation is cooled to room temperature, and then passedthrough a 12 mesh screen. After screening, the granulation is placed inthe Collette Mixer and lubricated with talc and magnesium stearate whilemixing. The granulation is compressed at the appropriate weight.

The appropriate amount of film coating suspension is prepared bydispersing Opadry Blue YS-1-4026 in sufficient purified water and thenthe batch is film-coated in a rotary pan. After the tablets are coated,they are cured in an incubator at 45° C. for 48 hours.

Tablets of Comparative Example 13 (mean tablet weight 663.7 mg) are thensubjected to dissolution testing. The dissolution testing is carried outseparately with respect to the two drugs in the formulation, codeinephosphate and APAP, in order to determine the rate of in vitro releaseof each of these drugs from the formulation. The dissolution testing iscarried out via the USP Basket Method, as previously described. Theresults are set forth in Tables 23 and 24 below.

                  TABLE 23                                                        ______________________________________                                        COMPARATIVE EXAMPLE 13                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           24.6                                                              2           54.9                                                              4           92.3                                                              8           100.6                                                             12          101.5                                                             18          101.9                                                             24          102.4                                                             ______________________________________                                    

                  TABLE 24                                                        ______________________________________                                        COMPARATIVE EXAMPLE 13                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           40.1                                                              2           67.4                                                              4           96.6                                                              8           99.7                                                              12          100.1                                                             18          100.5                                                             24          101.2                                                             ______________________________________                                    

Dissolution tests were identically carried out for the tablets ofComparative Example 14 (mean tablet weight 680.7 mg). The results areset forth in Tables 25 and 26 below.

                  TABLE 25                                                        ______________________________________                                        COMPARATIVE EXAMPLE 14                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT ACETAMINOPHEN DISSOLVED                                                           Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           21.2                                                              2           38.2                                                              4           74.5                                                              8           97.8                                                              12          101.0                                                             18          100.9                                                             24          101.4                                                             ______________________________________                                    

                  TABLE 26                                                        ______________________________________                                        COMPARATIVE EXAMPLE 14                                                        CODEINE PHOS./APAP 45 MG/450 MG                                               CONTROLLED RELEASE MATRIX TABLETS                                             PERCENT CODEINE PHOSPHATE DISSOLVED                                                       Percent                                                           Hours       Dissolved (Mean)                                                  ______________________________________                                        1           37                                                                2           55.4                                                              4           89.3                                                              8           102.2                                                             12          102.7                                                             18          102.6                                                             24          102.4                                                             ______________________________________                                    

As can be readily ascertained from the results provided above, thebatch-to-batch in vitro dissolution variability for the formulation withrespect to the relatively soluble drug, codeine phosphate, wasacceptably small. However, the batch-to-batch in vitro dissolutionvariability for the formulation with respect to the relatively insolubledrug, APAP, was unacceptably large. This is shown graphically in Figures7 and 8. The in vitro dissolution results of Comparative Examples 13-14provide further confirmation with regard to the batch-to-batchdissolution variability problems which arise when attempting toformulate controlled release products of relatively insoluble drugs.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. A method for preparing an oral, sustained releaseformulation of an insoluble, therapeutically active agent,comprisingcoating an immediate release tablet core includingacetaminophen in an amount sufficient to render a therapeutic effectwith a controlled release coating on the tablet core comprising ahydrophobic material such that said formulation reproducibly provides adissolution rate in-vitro of the dosage form, when measured by the USPPaddle Method at 100 rpm in 900 ml aqueous buffer, pH between 1.6 andabout 7.2, at 37° C. between 12.5 and 42.5 (by wt) released after 1hour, between 25 and 56% (by wt) released after 2 hours, between 45 and75% (by wt) released after 4 hours, and between 55 and 85% (by wt)released after 6 hours.
 2. The method of claim 1, further comprisingselecting said hydrophobic material from the group consisting of wax,shellac, zein, fatty alcohols, hydrogenated vegetable oils, cellulosederivatives, acrylic polymers, and mixtures of any of the foregoing. 3.The method of claim 2, further comprising coating said tablet core withsaid hydrophobic material to a weight gain from about 3 to about 20percent, by weight.
 4. A method of treating a patient with a dose of apharmaceutical formulation containing acetaminophen over an extendedperiod of time, comprisingpreparing an immediate release solid tabletcore comprising acetaminophen in an amount sufficient to render atherapeutic effect; coating said tablet core with a hydrophobic materialselected from the group consisting of waxes, shellac, zein, fattyalcohols, hydrogenated vegetable oils, cellulose derivatives, acrylicpolymers and mixtures thereof, such that said formulation reproduciblyreleases acetaminophen at a dissolution rate between 12.5% and 42.5% (bywt) released after 1 hour, between 25% and 56% (by wt) released after 2hours, between 45% and 75% (by wt) released after 4 hours, between 55%and 85% (by wt) released after 6 hours when measured by the USP PaddleMethod at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at37° C., and administering said tablet to a patient.
 5. The method ofclaim 4, further comprising incorporating into said tablet an effectiveamount of a soluble therapeutically active agent selected from the groupconsisting of hydromorphone, oxycodone, dihydrocodeine, codeine,dihydromorphine, morphine, buprenorphine, salts of any of the foregoing,and mixtures of any of the foregoing.
 6. A method for preparing an oralsustained release formulation of acetaminophen, comprising coating animmediate release tablet core including acetaminophen in an amountsufficient to render a therapeutic effect, with a controlled releasecoating of a hydrophobic material selected from the group consisting ofwaxes, shellac, zein, fatty alcohols, hydrogenated vegetable oils,cellulose derivatives, acrylic polymers and mixtures thereof, such thatsaid formulation reproducibly provides an in-vitro dissolution rateindicative of a twice-a-day or once-a-day formulation.
 7. The method ofclaim 6, further comprising incorporating into said tablet an effectiveamount of a soluble therapeutically active agent selected from the groupconsisting of hydromorphone, oxycodone, dihydrocodeine, codeine,dihydromorphine, morphine, buprenorphine, salts of any of the foregoing,and mixtures of any of the foregoing.
 8. The method of claim 1, whereinsaid tablet releases said acetaminophen over a time period from about 12to about 24 hours when exposed to fluids in an environment of use.